The instant invention is concerned with N-substituted indoles having aryloxyalkanoic acid substituents, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, often referred to as non-insulin dependent diabetes (NIDDM), of conditions that are often associated with this disease, and of lipid disorders.
Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
The available treatments for type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide), which stimulate the pancreatic xcex2-cells to secrete more insulin, and/or by injection of insulin after the response to sulfonylureas fails, will result in high enough insulin concentrations to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from these last two treatments, and increasing insulin resistance due to the even higher plasma insulin levels can occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. However, the two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea, respectively.
The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a more recently described class of compounds with potential for a novel mode of action in preventing or ameliorating many symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia.
Disorders of lipid metabolism or dyslipidemias include various conditions characterized by abnormal concentrations of one or more lipids (i.e. cholesterol and triglycerides), and/or apolipoproteins (i.e., apolipoproteins A, B, C and E), and/or lipoproteins (i.e., the macromolecular complexes formed by the lipid and the apolipoprotein that allow lipids to circulate in blood, such as LDL, VLDL and IDL). Cholesterol is mostly carried in Low Density Lipoproteins (LDL), and this component is commonly known as the xe2x80x9cbadxe2x80x9d cholesterol because it has been shown that elevations in LDL-cholesterol correlate closely to the risk of coronary heart disease. A smaller component of cholesterol is carried in the High Density Lipoproteins and is commonly known as the xe2x80x9cgoodxe2x80x9d cholesterol. In fact, it is known that the primary function of HDL is to accept cholesterol deposited in the arterial wall and to transport it back to the liver for disposal through the intestine. Although it is desirable to lower elevated levels of LDL cholesterol, it is also desirable to increase levels of HDL cholesterol. Generally, it has been found that increased levels of HDL are associated with lower risk for coronary heart disease (CHD). See, for example, Gordon, et al., Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N. England J. Med., 325, 373-381 (1991); and Kannel, et al., Ann. Internal Med., 90, 85-91 (1979). An example of an HDL raising agent is nicotinic acid, a drug with limited utility because doses that achieve HDL raising are associated with undesirable effects, such as flushing.
Dyslipidemias were originally classified by Fredrickson according to the combination of alterations mentioned above. The Fredrickson classification includes 6 phenotypes (i.e., I, IIa, IIb, III, IV and V) with the most common being the isolated hypercholesterolemia (or type IIa) which is usually accompained by elevated concentrations of total and LDL cholesterol. The initial treatment for hypercholesterolemia is often to modify the diet to one low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy when LDL-lowering goals are not met by diet and exercise alone
A second common form of dyslipidemia is the mixed or combined hyperlipidemia or type IIb and III of the Fredrickson classification. This dyslipidemia is often prevalent in patients with type 2 diabetes, obesity and the metabolic syndrome. In this dyslipidemia there are modest elevations of LDL-cholesterol, accompanied by more pronounced elevations of small dense LDL-cholesterol particles, VLDL and/or IDL (i.e., triglyceride rich lipoproteins), and total triglycerides. In addition, concentrations of HDL are often low.
Peroxisome proliferators are a structurally diverse group of compounds that when administered to rodents elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes of the beta-oxidation cycle. Compounds of this group include but are not limited to the fibrate class of lipid modulating drugs, herbicides and phthalate plasticizers. Peroxisome proliferation is also triggered by dietary or physiological factors such as a high-fat diet and cold acclimatization.
Three sub-types of peroxisome proliferator activated receptor (PPAR) have been discovered and described; they are peroxisome proliferator activated receptor alpha (PPARxcex1), peroxisome proliferator activated receptor gamma (PPARxcex3) and peroxisome proliferator activated receptor delta (PPARxcex4). Identification of PPARxcex1, a member of the nuclear hormone receptor superfamily activated by peroxisome proliferators, has facilitated analysis of the mechanism by which peroxisome proliferators exert their pleiotropic effects. PPARxcex1 is activated by a number of medium and long-chain fatty acids, and it is involved in stimulating xcex2-oxidation of fatty acids. PPARxcex1 is also associated with the activity of fibrates and fatty acids in rodents and humans. Fibric acid derivatives such as clofibrate, fenofibrate, benzafibrate, ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil, each of which are PPARxcex1 ligands and/or activators, produce a substantial reduction in plasma triglycerides as well as some increase in HDL. The effects on LDL cholesterol are inconsistent and might depend upon the compound and/or the dyslipidemic phenotype. For these reasons, this class of compounds has been primarily used to treat hypertriglyceridemia (i.e, Fredrickson Type IV and V) and/or mixed hyperlipidemia.
The PPARxcex3 receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver. There are two known protein isoforms of PPARxcex3 PPARxcex31 and PPARxcex32 which differ only in that PPARxcex32 contains an additional 28 amino acids present at the amino terminus. The DNA sequences for the human isotypes are described in Elbrecht, et al., BBRC 224;431-437 (1996). In mice, PPARxcex32 is expressed specifically in fat cells. Tontonoz et al., Cell 79: 1147-1156 (1994) provide evidence to show that one physiological role of PPARxcex32 is to induce adipocyte differentiation. As with other members of the nuclear hormone receptor superfamily, PPARxcex32 regulates the expression of genes through interaction with other proteins and binding to hormone response elements, for example in the 5xe2x80x2 flanking regions of responsive genes. An example of a PPARxcex32 responsive gene is the tissue-specific adipocyte P2 gene. Although peroxisome proliferators, including the fibrates and fatty acids, activate the transcriptional activity of PPAR""s, only prostaglandin J2 derivatives have been identified as potential natural ligands of the PPARxcex3 subtype, which also binds thiazolidinedione antidiabetic agents with high affinity.
The human nuclear receptor gene PPARxcex4 (hPPARxcex4) has been cloned from a human osteosarcoma cell cDNA library and is fully described in A. Schmidt et al., Molecular Endocrinology, 6:1634-1641 (1992). It should be noted that PPARxcex4 is also referred to in the literature as PPARxcex2 and as NUC1, and each of these names refers to the same receptor; in Schmidt et al. the receptor is referred to as NUC1.
In WO96/01430, a human PPAR subtype, hNUC1B, is disclosed. The amino acid sequence of hNUC1B differs from human PPARxcex4 (referred to therein as hNUC1) by one amino acid, i.e., alanine at position 292. Based on in vivo experiments described therein, the authors suggest that hNUC1B protein represses hPPARxcex1 and thyroid hormone receptor protein activity.
It has been disclosed in WO97/28149 that agonists of PPARxcex4 are useful in raising HDL plasma levels. WO97/27857, 97/28115, 97/28137 and 97/27847 disclose compounds that are useful as antidiabetic, antiobesity, anti-artherosclerosis and antihyperlipidemic agents, and which may exert their effect through activation of PPARs.
It is generally believed that glitazones exert their effects by binding to the peroxisome proliferator activated receptor (PPAR) family of receptors, controlling certain transcription elements having to do with the biological entities listed above. See Hulin et al., Current Pharm. Design (1996) 2, 85-102. In particular, PPARxcex3 has been implicated as the major molecular target for the glitazone class of insulin sensitizers.
A number of glitazones that are PPAR agonists have been approved for use in the treatment of diabetes. These are troglitazone, rosiglitazone and pioglitazone, all of which are primarily or exclusively PPARxcex3 agonists. Although glitazones are beneficial in the treatment of NIDDM, there have been some serious adverse events associated with the use of the compounds. The most serious of these has been liver toxicity, which has resulted in a number of deaths. The most serious problems have occurred using troglitazone, which was recently withdrawn from the market because of toxicity concerns.
In addition to potential hepatotoxicity, there are several shortcomings associated with the glitazones: (1) Monotherapy for NIDDM produces modest efficacyxe2x80x94reductions in average plasma glucose of ≈20% or a decline from ≈9.0% to ≈8.0% in HemoglobinA1C. (2) There is room for improvement in lipid effects; troglitazone causes a slight increase in LDL cholesterol, and triglyceride lowering is modest relative to the effect of fibrates; results reported to date with rosiglitazone suggest no effect on triglycerides and a possible net increase in the LDL:HDL ratio. Currently available data on pioglitazone appear to indicate that it lowers triglycerides modestly and may also have a neutral or positive effect on LDL vs. HDL (i.e. slight HDL raising with no effect on LDL). (3) All three glitazones have been associated with significant weight gain as well as other AE""s (mild edema and mild anemia). These shortcomings provide an opportunity to develop better insulin sensitizers for Type 2 diabetes which function via similar mechanism(s) of action.
Because of the problems that have occurred with the glitazones, researchers in a number of laboratories have been investigating classes of PPAR agonists that are not glitazones and do not contain 1,3-thiazolidinedione moieties, but that modulate the three known PPAR subtypes, in concert or in isolation, to varying degrees (as measured by intrinsic potency, maximal extent of functional reponse or spectrum of changes in gene expression). Such classes of compounds are expected to be useful in the treatment of diabetes and associated conditions, dyslipidemias and associated conditions and several other indications and may be free of some of the side effects that have been found in many of the glitazones.
The class of compounds described herein is a new class of PPAR agonists that do not contain a 1,3-thiazolidinedione moiety and therefore are not glitazones. The class of compounds includes compounds that are primarily PPARxcex3 agonists and PPARxcex3 partial agonists. Some compounds may also have PPARxcex1 activity in addition to the PPARxcex3 activity, so that the compounds are mixed PPARxcex1/xcex3 agonists. These compounds are useful in the treatment, control and/or prevention of diabetes, hyperglycemia, and insulin resistance. The compounds of the invention exhibit reduced side effects relating to body and heart weight gain in preclinical animal studies compared with other PPARxcex3 compounds including rosiglitazone.
The compounds may also be useful in the treatment of mixed or diabetic dyslipidemia and other lipid disorders (including isolated hypercholesterolemia as manifested by elevations in LDL-C and/or non-HDL-C and/or hyperapoBliproteinemia, hypertriglyceridemia and/or increase in triglyceride-rich-lipoproteins, or low HDL cholesterol concentrations), atherosclerosis, obesity, vascular restenosis, inflammatory conditions, neoplastic conditions, psoriasis, polycystic ovary syndrome and other PPAR mediated diseases, disorders and conditions.
The present invention is directed to compounds of formula I: 
wherein:
R1 is methyl, optionally substituted with 1-3 F;
R2, R3 and R4 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, OC1-C6 alkyl, OC2-C6 alkenyl, OC2-C6 alkynyl, O-aryl, OH, SC1-C6 alkyl, SC2-C6 alkenyl, SC2-C6 alkynyl, SO2C1-C6 alkyl, SO2C2-C6 alkenyl, SO2C2-C6 alkynyl,OCON(R5)2, OCO(C1-C6-alkyl) and CN, wherein all instances of alkyl, alkenyl and alkynyl are optionally linear or branched and all instances of alkyl, alkenyl, alkynyl, cycloalkyl and aryl are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, aryl, O-aryl and OMe;
R5 and R6 are, at each occurrence, independently selected from the group consisting of H, F, OH and C1-C5 alkyl, and R5 and R6 groups that are on the same carbon atom optionally may be joined to form a C3-C6 cycloalkyl group;
R7 and R8 are each independently selected from the group consisting of H, F, and C1-5 alkyl, or R7 and R8 optionally may be joined to form a C3-C6 cycloalkyl group;
R9 is selected from the group consisting of H and C1-C5 alkyl, said alkyl being optionally linear or branched;
Ar1 is phenyl, 1-naphthyl, 2-naphthyl, pyridyl or quinolyl wherein Ar1 is substituted with 1-3 groups independently selected from R4;
X is selected from the group consisting of Cxe2x95x90O, S(O)2, CH2, CH(CH3), C(CH3)2, CF2, and cyclopropylidene;
Y is O or S; and
n is 0-5;
and pharmaceutically acceptable salts and prodrugs thereof.
The present compounds are effective in lowering glucose, lipids, and insulin in diabetic animals and lipids in non-diabetic animals. The compounds are expected to be efficacious in the treatment, control and/or prevention of non-insulin dependent diabetes mellitus (NIDDM) in humans and in the treatment, control, and/or prevention of conditions associated with NIDDM, including hyperlipidemia, dyslipidemia, obesity, hypercholesterolemia, hypertrigyceridemia, atherosclerosis, vascular restenosis, inflammatory conditions, neoplastic conditions, and other PPAR mediated diseases, disorders and conditions.
The invention has numerous embodiments. It provides compounds of formula I, including pharmaceutically acceptable salts of these compounds, prodrugs of these compounds, and pharmaceutical compositions comprising any of the compounds described and a pharmaceutically acceptable carrier.
In one embodiment, in compounds having the formula I, R1 is CH3.
In another embodiment of compounds having the formula I, R1 is CH3;
R2, R3, and R4 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, OC1-C6 alkyl, OC2-Cb alkenyl, OC2-C6 alkynyl, O-aryl, OH, SC1-C6 alkyl, SC2-C6 alkenyl, SC2-C6 alkynyl, OCON(R5)2, OCO(C1-C6-alkyl) and CN, wherein all instances of alkyl, alkenyl and alkynyl are optionally linear or branched and all instances of alkyl, alkenyl, alkynyl, cycloalkyl and aryl are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, aryl, O-aryl and OMe; and
X is selected from the group consisting of Cxe2x95x90O, CH2, CH(CH3), C(CH3)2, CF2, and cyclopropylidene.
In another embodiment, in compounds having the formula I, R2, R3, and R4 are each independently selected from the group consisting of H, OCH3, OCF3, F, Cl and CH3, where CH3 is optionally substituted with 1-3 groups independently selected from F, Cl, and OCH3. In more specific embodiments, R2, R3, and R4 are each independently selected from the group consisting of H, OCH3, OCF3, and Cl.
In another group of compounds having the formula I, R5 and R6 are H.
In another group of compounds having the formula I, R7 and R8 are each independently CH3 or H.
In preferred groups of compounds having the formula I, R9 is H.
In other compounds having formula I, X is Cxe2x95x90O.
In other compounds having formula I, Y is O.
In another group of compounds having formula I, n is 0, 1, or 2. In a more specific subset of this group of compounds, n is 1.
Another group of compounds having formula I includes compounds in which Ar1 is phenyl, 1-naphthyl or 2-naphthyl. A subset of this group of compounds includes compounds in which Ar1 is phenyl or 2-naphthyl. In either case, Ar1 is substituted with 1-3 groups independently selected from R4.
In preferred groups of compounds, aryl substituents are phenyl groups.
A preferred set of compounds having formula I has the following substituents:
R1 is CH3;
R2 is selected from the group consisting of H, OCH3, and OCF3;
R3, R5, R6, and R9 are H;
R4 is selected from the group consisting of H, Cl, and OCH3;
R7 and R8 are each independently selected from the group consisting of H and CH3;
X is Cxe2x95x90O;
Y is O;
and n is l.
Specific examples of compounds of this invention are provided as Examples 1-31, named below: